Anticoagulant

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Antithrombotic agents
Drug class
ATC codeB01
External links
MeSHD005343
AHFS/Drugs.comDrug Classes
 
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Antithrombotic agents
Drug class
ATC codeB01
External links
MeSHD005343
AHFS/Drugs.comDrug Classes

Anticoagulants (antithrombics, fibrinolytic, and thrombolytics) are a class of drugs that work to prevent the coagulation (clotting) of blood. Such substances occur naturally in leeches and blood-sucking insects. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis equipment.

Medications[edit]

Anticoagulants reduce blood clotting. This prevents deep vein thrombosis, pulmonary embolism, myocardial infarction and ischemic stroke.

Coumarins (vitamin K antagonists)[edit]

These oral anticoagulants are derived from coumarin, which is found in many plants. A prominent member of this class is warfarin (Coumadin). It takes at least 48 to 72 hours for the anticoagulant effect to develop. Where an immediate effect is required, heparin must be given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves.

Adverse effects[edit]

Patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years.[1] These oral anticoagulants are used widely as poisons for mammalian pests, especially rodents. (For details, see rodenticide and warfarin.) Depletion of vitamin K by Coumadin therapy increases risk of arterial calcification and heart valve calcification, especially if too much vitamin D is present.[2]

Available agents[edit]

Heparin and derivative substances[edit]

Heparin is a biological substance, usually made from pig intestines. It works by activating antithrombin III, which blocks thrombin from clotting blood. Heparin can be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in or on medical devices. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually have a green cap.

Major pharmaceutical heparin recall due to contamination[edit]

In March 2008, major recalls of heparin were announced by pharmaceutical companies due to a suspected and unknown contamination of the raw heparin stock imported from China.[4][5] The contaminant was later found to be a compound called oversulfated chondroitin sulfate.[6] The US Food and Drug Administration was quoted as stating at least 19 deaths were believed linked to a raw heparin ingredient imported from the People's Republic of China, and they had also received 785 reports of serious injuries associated with the drug’s use. According to the New York Times: 'Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock'.

Low molecular weight heparin[edit]

Low molecular weight heparin, a more highly processed product, is useful as it does not require monitoring of the APTT coagulation parameter (it has more predictable plasma levels) and has fewer side effects.

Synthetic pentasaccharide inhibitors of factor Xa[edit]

Direct factor Xa inhibitors[edit]

Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike the heparins and fondaparinux, which work via antithrombin activation). Also betrixaban (LY517717) from Portola Pharmaceuticals, darexaban (YM150) from Astellas and more recent TAK-442 letaxaban (Takeda) and eribaxaban (PD0348292) (Pfizer). The development of darexaban was discontinued in September 2011: in a trial for prevention of recurrences of myocardial infarction in top of dual antiplatelet therapy, the drug didn't work and the risk for bleeding was increased bij 300%.[7] The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following negative results from a Phase II study.[8]

Direct thrombin inhibitors[edit]

Another type of anticoagulant is the direct thrombin inhibitor.[9] Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin; and the monovalent drugs argatroban and dabigatran. An oral direct thrombin inhibitor, ximelagatran (Exanta) was denied approval by the Food and Drug Administration (FDA) in September 2004 [1] and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. [2] In November 2010, dabigatran was approved by the FDA to treat atrial fibrillation.

Antithrombin protein therapeutics[edit]

The antithrombin protein itself is used as a protein therapeutic that can be purified from human plasma[10] or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats.[11][12])

Antithrombin is approved by the FDA as an anticoagulant for the prevention of clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.[10][12]

Other types of anticoagulants[edit]

Many other anticoagulants exist, for use in research and development, diagnostics, or as drug candidates.

Food and herbal supplements[edit]

Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John’s wort, turmeric, wheatgrass, and willow bark.[13] Many herbal supplements have blood-thinning properties, such as danshen and feverfew. Multivitamins that do not interact with clotting are available for patients on anticoagulants.

However, some foods and supplements encourage clotting. These include alfalfa, avocado, cat's claw, coenzyme Q10, and dark leafy greens such as spinach. Their intake should be avoided whilst taking anticoagulants or, if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability.

Grapefruit interferes with some anticoagulant drugs, increasing the amount of time it takes for them to be metabolized out of the body, and so should be eaten only with caution when on anticoagulant drugs.

General indications[edit]

Therapeutic uses of anticoagulants include atrial fibrillation, pulmonary embolism, deep vein thrombosis, venous thromboembolism, congestive heart failure, stroke, myocardial infarction, and genetic or acquired hypercoagulability.

Laboratory use[edit]

Laboratory instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and become nonoperational if blood is allowed to clot. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Apart from heparin, most of these chemicals work by binding calcium ions, preventing the coagulation proteins from using them.

See also[edit]

References[edit]

  1. ^ Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S (2007). "Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation". Circulation 115 (21): 2689–96. doi:10.1161/CIRCULATIONAHA.106.653048. PMID 17515465. 
  2. ^ Adams J, Pepping J (1 Aug 2005). "Vitamin K in the treatment and prevention of osteoporosis and arterial calcification". American Journal of Health-System Pharmacy 62 (15): 1574–81. doi:10.2146/ajhp040357. PMID 16030366. Retrieved 2012-10-03. 
  3. ^ Ron Winslow; Avery Johnson (2007-12-10). "Race Is on for the Next Blood Thinner". Wall Street Journal. p. A12. Retrieved 2008-01-06. "...in a market now dominated by one of the oldest mainstay pills in medicine: the blood thinner warfarin. At least five next-generation blood thinners are in advanced testing to treat or prevent potentially debilitating or life-threatening blood clots in surgery and heart patients. First candidates could reach the market in 2009." 
  4. ^ New York Times, March 6, 2008 Drug Tied to China Had Contaminant, F.D.A. Says, retrieved 2008-03-07
  5. ^ New York Times, March 7, 2008 German Authorities Report Problems With Blood Thinner, retrieved 2008-03-07
  6. ^ Blossom, DB; Kallen, AJ; Patel, PR; Elward, A; Robinson, L; Gao, G; Langer, R; Perkins, KM et al. (2008). "Outbreak of adverse reactions associated with contaminated heparin". N Engl J Med. 359 (25): 2674–84. doi:10.1056/NEJMoa0806450. PMID 19052120. 
  7. ^ Steg, PG; Mehta, SR; Jukema, JW; Lip, GY; Gibson, CM; Kovar, F; Kala, P; Garcia-Hernandez, A; Renfurm, RW; Granger, CB; Ruby-1, Investigators (2011). "RUBY-1: A randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome". European heart journal 32 (20): 2541–54. doi:10.1093/eurheartj/ehr334. PMC 3295208. PMID 21878434. 
  8. ^ First Time European Approval for Xarelto in ACS http://decisionresources.com/The-Decision-Resources-Blog/May-2013/European-Approval-for-Xarelto-in-ACS-052913
  9. ^ Di Nisio M, Middeldorp S, Büller HR (2005). "Direct thrombin inhibitors". N. Engl. J. Med. 353 (10): 1028–40. doi:10.1056/NEJMra044440. PMID 16148288. 
  10. ^ a b Thrombate III label
  11. ^ FDA website for ATryn (BL 125284)
  12. ^ a b Antithrombin (Recombinant) US Package Insert ATryn for Injection February 3, 2009
  13. ^ Wittkowsky AK (September 2001). "Drug interactions update: drugs, herbs, and oral anticoagulation". J. Thromb. Thrombolysis 12 (1): 67–71. doi:10.1023/A:1012742628628. PMID 11711691. 

External links[edit]